Clinical Trials Logo

Clinical Trial Summary

It has been suggested that mitochondrial dysfunction might play a role in the development of diabetic cardiomyopathy. From animal studies, it has been suggested that an altered PPAR and PGC1 expression is involved in the reduced cardiac mitochondrial function, however human data on cardiac mitochondrial function and PPAR regulation is scarce. The latter is due to the fact that there is no validated measurement for assessing cardiac mitochondrial function non-invasively in vivo. It has been suggested that measuring PCr/ATP ratio with 31P-MRS in the heart reflects cardiac mitochondrial function. However, so far no direct validation of this method has been performed. The aim of this study will be to validate in vivo 31P-MRS with ex vivo measurements of mitochondrial function. To this end, the hypothesis is that in vivo 31P-MRS is a valid method for measuring cardiac mitochondrial function when compared with ex vivo mitochondrial respirometry.


Clinical Trial Description

Cardiovascular diseases remain the main cause of death in type 2 diabetes. Most of this is attributed to atherosclerosis and elevated blood pressure, though even when corrected for these factors, patients with type 2 diabetes are still at increased risk for developing cardiac failure, mainly through diastolic dysfunction. This phenomenon has also been described as diabetic cardiomyopathy. Although not much is known about the aetiology of this disease, there is compelling evidence from animal research that an increased intracellular cardiac fat accumulation and mitochondrial dysfunction, as seen in type 2 diabetes, may play a part in this development. The reason for a reduced mitochondrial function in diabetic cardiomyopathy is not completely understood, however the gene regulatory pathway of peroxisome proliferator-activated receptor alpha (PPAR-α) has been identified as an important determinant of the shift in substrate metabolism and regulation of oxidative metabolism in type 2 diabetes. In animal studies, the role of PPARα has been tested extensively. In mice with cardiac-restricted overexpression of PPARα (MHC-PPAR), it was found that PPAR-α is involved in the upregulation of CPT-1 in mitochondria, which increases the uptake of long-chain fatty acid into mitochondria and facilitates the fatty acids to undergo beta-oxidation. Chronic exposure to elevated FFAs down regulates PPAR-α in rodent cardiomyocytes, which would further decrease cardiac function by inhibition of FA oxidation and increased intracellular fat accumulation. It is therefore speculated that the increase in fatty acid availability in type 2 diabetes and obesity (due to excessive fat mass) leads to a decrease in cardiac PPAR-α metabolism and thereby a decrease in mitochondrial metabolism, which in turn is paralleled by an increased cardiac fat accumulation and cardiac lipotoxicity. So far, human studies on PPAR expression in the heart are scarce. Marfella et al. found unaltered expression of PPAR-α in patients with the metabolic syndrome. Conversely, Anderson et al., showed a slightly reduced PPAR-α protein level and a slightly higher PGC1α level in diabetic atrial tissue, though these differences did not reach statistical significance in this cohort of patients. As this study was performed in a small group of subjects and failed to determine the down-stream targets of the PPAR metabolism or mitochondrial function, it remains unclear whether like in animal studies also in humans a reduced PPAR-a expression is related to mitochondrial dysfunction. Therefore there is need for studies exploring the role of PPAR-a in human heart and the connections with oxidative metabolism and cardiac function. Mice lacking the cardiac lipase ATGL (ATGL-/- mice) was actually due to a reduction in PPAR metabolism, and that the cardiomyopathy in these mice could be completely prevented by treating these animals with synthetic PPAR-a ligands. Very interestingly, patients with a mutation in the same ATGL gene are also characterized by excessive cardiac and muscle fat accumulation and reduced mitochondrial function. Treating two patients with such mutations (which is a very rare mutation) with a PPAR-agonist (bezafibrate) resulted in improved mitochondrial function and a reduction in muscle and cardiac lipid accumulation. These data support the notion that a disturbed PPAR metabolism may be involved in the development of cardiomyopathy, also in humans. However, unfortunately, there is limited data on PPAR-expression in the failing human diabetic heart. Therefore there is need of studies validating these mechanisms in humans, as these findings might have great consequences; prevention and treatment of cardiac lipid accumulation with drugs that improve mitochondrial function, such as PPAR-agonists, might be of value to patients with type 2 diabetes. Also in other cardiac diseases, such as chronic heart failure and ischemic heart disease, it has been suggested that fat accumulation and mitochondrial dysfunction may play a role, which means that these patients might benefit as well from treatment with drugs that target mitochondrial function. Although there is compelling evidence that mitochondrial function plays an important role in cardiac metabolism, measuring cardiac mitochondrial function non-invasively in vivo remains a challenge. In vivo mitochondrial function can be estimated non-invasively with 31P-Magnetic Resonance Spectroscopy (31P-MRS), whereby the ratio Phospho-creatine (PCr) over Adenosine Triphosphate (ATP) is measured (PCr/ATP-ratio). Several studies have shown that this ratio is reduced in patients with type 2 diabetes, and that a low PCr/ATP ratio predicts mortality in patients with cardiac failure15-17. In skeletal muscle it has been shown that PCr-resynthesis strongly correlates with mitochondrial oxidative capacity18. However, if this method in the heart truly reflects mitochondrial function in humans has not been revealed. In 31P-MRS a 2 dimensional measurement method is used, in which multiple slices are planned over the heart. One slice is planned directly at the base of the heart in the plane just below the valves and contains both ventricular and septal tissue of both chambers. Here the signal for acquisition of the spectrum will be derived. This method can be validated against the golden standard for mitochondrial function: ex vivo respirometry of cardiac tissue19. Thus, mitochondrial respiration rates are measured in tissue homogenates under exposure of different substrates, stimulating different complexes of the electron transport chain of the mitochondria. One issue is that mitochondrial respiration may differ between atrial and ventricular tissue. However, despite the differences in absolute respiration rates, the behaviour of the different complexes and relative respiration rates (between complexes) has been shown to be very strongly related19. Since it is relatively easy to obtain atrial appendage cardiac tissue during surgery, the investigators propose to use atrial tissue obtained during surgery to validate 31P-MRS as a tool to determine mitochondrial function. The investigators will use a broad range of patients to guarantee a range in cardiac mitochondrial functions, and to examine if cardiac mitochondrial function is indeed reduced in type 2 diabetic patients. However, as the 31P-MRS still is a technique in development and the distance to the receiver coil is crucial for obtaining spectra of good quality, the investigators intend to only include men at this time (as increased breast mass in women may decrease signal to noise ratios and hence spectral quality for analysis). Therefore, the validation of this method will only apply for the male population in this study. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT03049228
Study type Observational [Patient Registry]
Source Maastricht University Medical Center
Contact
Status Completed
Phase
Start date March 21, 2017
Completion date March 2, 2020

See also
  Status Clinical Trial Phase
Active, not recruiting NCT05666479 - CGM Monitoring in T2DM Patients Undergoing Orthopaedic Replacement Surgery
Completed NCT05647083 - The Effect of Massage on Diabetic Parameters N/A
Active, not recruiting NCT05661799 - Persistence of Physical Activity in People With Type 2 Diabetes Over Time. N/A
Completed NCT03686722 - Effect of Co-administration of Metformin and Daclatasvir on the Pharmacokinetis and Pharmacodynamics of Metformin Phase 1
Completed NCT02836704 - Comparison of Standard vs Higher Starting Dose of Insulin Glargine in Chinese Patients With Type 2 Diabetes (Glargine Starting Dose) Phase 4
Completed NCT01819129 - Efficacy and Safety of FIAsp Compared to Insulin Aspart in Combination With Insulin Glargine and Metformin in Adults With Type 2 Diabetes Phase 3
Completed NCT04562714 - Impact of Flash Glucose Monitoring in People With Type 2 Diabetes Using Non-Insulin Antihyperglycemic Therapy N/A
Completed NCT02009488 - Treatment Differences Between Canagliflozin and Placebo in Insulin Secretion in Subjects With Type 2 Diabetes Mellitus (T2DM) Phase 1
Completed NCT05896319 - Hyaluronic Acid Treatment of the Post-extraction Tooth Socket Healing in Subjects With Diabetes Mellitus Type 2 N/A
Recruiting NCT05598203 - Effect of Nutrition Education Groups in the Treatment of Patients With Type 2 Diabetes N/A
Completed NCT05046873 - A Research Study Looking Into Blood Levels of Semaglutide and NNC0480-0389 When Given in the Same Injection or in Two Separate Injections in Healthy People Phase 1
Terminated NCT04090242 - Impact of App Based Diabetes Training Program in Conjunction With the BD Nano Pen Needle in People With T2 Diabetes N/A
Completed NCT04030091 - Pulsatile Insulin Infusion Therapy in Patients With Type 1 and Type 2 Diabetes Mellitus Phase 4
Completed NCT03620357 - Continuous Glucose Monitoring & Management In Type 2 Diabetes (T2D) N/A
Completed NCT03604224 - A Study to Observe Clinical Effectiveness of Canagliflozin 300 mg Containing Treatment Regimens in Indian Type 2 Diabetes Participants With BMI>25 kg/m^2, in Real World Clinical Setting
Completed NCT01696266 - An International Survey on Hypoglycaemia Among Insulin-treated Patients With Diabetes
Completed NCT03620890 - Detemir Versus NPH for Type 2 Diabetes Mellitus in Pregnancy Phase 4
Withdrawn NCT05473286 - A Research Study Looking at How Oral Semaglutide Works in People With Type 2 Diabetes in Germany, as Part of Local Clinical Practice
Not yet recruiting NCT05029804 - Effect of Walking Exercise Training on Adherence to Disease Management and Metabolic Control in Diabetes N/A
Completed NCT04531631 - Effects of Dorzagliatin on 1st Phase Insulin and Beta-cell Glucose Sensitivity in T2D and Monogenic Diabetes Phase 2